Halobetasol foam composition and method of manufacture thereof

ABSTRACT

The present invention provides a method of manufacturing foamable, corticosteroid containing compositions as well as methods for treating various skin diseases.

RELATED APPLICATION DATA

This application is a continuation of U.S. patent application Ser.No.15/874,610, filed Jan. 18, 2018; which is a divisional of U.S. patentapplication Ser. No. 15/365,152, filed Nov. 30, 2016; which claims thebenefit of priority under 35 U.S.C. § 119(e) of U.S. Provisional PatentApplication Ser. No. 62/267,773, filed Dec. 15, 2015, the entirecontents of which is incorporated herein by reference in its entirety.

BACKGROUND Field of Invention

This invention relates to foamable compositions including acorticosteroid, and more particularly to a method of manufacturingstable foamable compositions.

Background Information

Corticosteroids are well known anti-inflammatory compounds, which arerecognizably utilized in the treatment of inflammatory diseases such asallergic contact dermatitis, eczema, asteatotic eczema, discoid eczema,infantile eczema and diaper dermatitis, psoriasis; including plaquepsoriasis, palmoplantar psoriasis, etc., seborrheic dermatitis, atopicdermatitis, dermatitis herpetiformis, neurodermatitis, lichen simplexchronicus, lichen planus, subacute cutaneous lupus erythematosus,urticaria, discoid lupus erythematosus, chronic hypertrophic lichenplanus, granuloma annulare, keloid scars, reactions to insect and spiderbites, pityriasis rosea, erythema, and pruritus. Formulations containingsuch active substances have conventionally been applied to the skin sitein the form of foams, ointments, gels, creams, sprays and lotions.

Foamable compositions are particularly desirable for topical applicationof cortico steroids. However, a number of problems exist in conventionalmethods of manufacturing cortico steroid foams, such as degradation andinactivation of the corticosteroid during manufacture and canning of thefoam composition. Additional problems include cortico steroiddegradation over the shelf life of the composition.

As such, there exists a need in the treatment of skin disordersrequiring treatment with cortico steroids for improved formulationsmanufactured by methods which prevent degradation and inactivation ofthe corticosteroid and which exhibit prolonged stability of the corticosteroid thereby exhibiting extended shelf life as compared toconventional foam compositions manufactured by conventional means.

SUMMARY

The manufacturing method and foamable compositions produced by suchmethod as presented herein do not utilize a traditional buffer systemwhich adds manufacturing complexity. However, compositions manufacturedby the presently described method exhibit a stable pH, enhancedstability of cortico steroids, and enhanced efficacy in treatment ascompared to other treatment options.

The compositions of the present invention demonstrate a clinicalefficacy which is superior to comparable corticosteroid containingcompositions. In addition, it has been found that the compositions ofthe present invention are stable and demonstrate very good long termstorage stability.

As will be further explained herein below, compositions manufactured bythe presently described method achieve a high level of clinical efficacywithout appreciably reducing transepidermal water loss (TEWL). Skinconductance studies have also demonstrated that the compositions of thepresent invention do not appreciably increase skin hydration. Thecompositions of the present invention comprise particular combinationsof ingredients which interact synergistically to produce the enhancedresults described herein without increasing skin hydration or reducingtransepidermal water loss.

Accordingly, in one aspect, the present invention provides a method forsingle-stream manufacture of a foamable composition including acorticosteroid. The method includes forming a homogenous solution whichincludes: i) an aliphatic alcohol; ii) a can corrosion inhibitor; iii) apolyol; iv) at least one foam structuring agent comprising one or morefatty alcohols, non-ionic surfactants, or combinations thereof; and v)water. In embodiments, the solution is formed in a single batch vesselat a constant temperature of between about 55°-75° C. while minimizingevaporative losses. Subsequently, the mixture is cooled to a temperatureof between about 40°-55° C. and a corticosteroid is then added to thesolution and mixed to homogeneity while maintaining a temperature ofbetween about 40°-55° C. The solution is then filled into dispensingcanisters while the solution is maintained at a temperature of betweenabout 40°-50° C. The filled canisters are then charged with a propellantthereby forming a single-phase foamable composition.

In another aspect, the present invention provides a greater than36-month storage stable, corticosteroid containing foamable compositionproduced by the method of manufacture described herein. The compositionincludes: a) a corticosteroid, or its pharmaceutically acceptable salts,esters, and solvates; b) an aliphatic alcohol; c) at least one foamstructuring agent (including one or more fatty alcohols, one or morenon-ionic surfactants, or combinations thereof); d) a polyol; e) water;f) a can corrosion inhibitor; and g) a propellant. In embodiments, thecomposition is void of a buffer.

In one embodiment, the present invention is a stable, therapeuticallyeffective composition consisting essentially of: a) halobetasol or itspharmaceutically acceptable salts, esters, and solvates; b) an aliphaticalcohol; c) at least one foam structuring agent selected from one ormore fatty alcohols, one or more non-ionic surfactants, or combinationsthereof; d) a polyol; f) water; and g) optionally, if the composition isstored in a metal container or can, benzoic acid as a can corrosioninhibitor. The composition is devoid of a buffer. The composition may bedevoid of a second therapeutic agent in addition to halobetasol.

In another embodiment, the present invention is a stable compositionconsisting of: a) halobetasol or its pharmaceutically acceptable salts,esters, and solvates; b) an aliphatic alcohol; c) at least one foamstructuring agent selected from one or more fatty alcohols, one or morenon-ionic surfactants, or combinations thereof; d) a polyol; f) water;and g) optionally, if the composition is stored in a metal container orcan, benzoic acid as a can corrosion inhibitor. The composition isdevoid of a buffer. The composition may be devoid of a secondtherapeutic agent in addition to halobetasol.

In another aspect, the present invention provides a method for treatinga subject having, or at risk of having, a corticosteroid-responsivecondition, such as a skin disease or disorder. The method includestopically administering to the subject in need thereof a foamablecomposition of the present invention, thereby treating thecorticosteroid-responsive condition. In some embodiments, the conditionis a skin disorder or disease, such as a corticosteroid-responsivedermatosis, including for example, atopic dermatitis, seborrheicdermatitis, contact dermatitis, psoriasis, atopic eczema, infantileeczema, discoid eczema, lichen simplex, lichen planus, skininflammation, miliaria, pityriasis rosea, erythema, and pruritus.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation presenting clinical data relatingto administration of compositions of the present invention in oneembodiment of the invention.

FIG. 2 is a graphical representation presenting clinical data relatingto administration of compositions of the present invention in oneembodiment of the invention.

FIG. 3 is a graphical representation presenting stability data relatingto the projected shelf-life of the compositions of the present inventionin one embodiment of the invention, based on assaying the activeingredient.

FIG. 4 is a graphical representation presenting stability data relatingto the projected shelf-life of the compositions of the present inventionin one embodiment of the invention, based on assaying a degradationproduct of the active ingredient.

FIG. 5 is a graphical representation presenting stability data relatingto the pH of the compositions of the present invention in one embodimentof the invention.

DETAILED DESCRIPTION

Before the present compositions and methods are further described, it isto be understood that this invention is not limited to particularcompositions, methods, and experimental conditions described, as suchcompositions, methods, and conditions may vary. It is also to beunderstood that the terminology used herein is for purposes ofdescribing particular embodiments only, and is not intended to belimiting, since the scope of the present invention will be limited onlyin the appended claims.

As used in this specification and the appended claims, the singularforms “a”, “an”, and “the” include plural references unless the contextclearly dictates otherwise. Thus, for example, references to “themethod” includes one or more methods, and/or steps of the type describedherein which will become apparent to those persons skilled in the artupon reading this disclosure and so forth.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the invention, the preferred methods andmaterials are now described.

Preparation and Canning

One aspect of the present invention is a process for manufacturing afoamable corticosteroid containing composition as described herein.Generally, the method includes forming a carrier solution by admixing analiphatic alcohol, a can corrosion inhibitor, one or more foamstructuring agents, such as a fatty alcohol and a non-ionic surfactant,a polyol, and water and heating to a temperature of at least 45° C.,more preferably at least 65° C., while minimizing evaporative losses.

According to a feature of the present invention, a corticosteroid isadded to the carrier at a temperature below 60° C., more preferablybelow 50° C. By adding corticosteroid at a lower temperature in themanufacturing process the rate of degradation of the corticosteroid ismarkedly reduced and thus the amount of degradant products is reduced.

According to yet another feature of the present invention thecorticosteroid containing solution is filled into canisters at atemperature above 35° C., most preferably above 42° C. Filled canistersare then charged with a propellant to produce a clear single-phasefoamable composition.

In particular, the method of the invention includes first forming ahomogenous carrier solution which includes: i) an aliphatic alcohol; ii)a can corrosion inhibitor; iii) a polyol; iv) at least one foamstructuring agent comprising one or more fatty alcohols, non-ionicsurfactants, or combinations thereof; and v) water. In embodiments, thesolution is formed in a single batch vessel at a constant temperature ofbetween about 55°-75° C., and more preferably between about 65°-70° C.,while minimizing evaporative losses.

In one embodiment, an aliphatic alcohol, such as ethanol, is firstheated in a single batch vessel to between about 65°-70° C. and a cancorrosion inhibitor, such as benzoic acid, is then added. The solutionis mixed to homogeneity and subsequently the following components areadmixed in series while maintaining a temperature of between about65°-70° C.: a polyol (e.g., propylene glycol); and foam structuringagents (e.g., combinations of Emulsifying wax, polyoxyl 20 cetostearylether, and cetostearyl alcohol). Water is added in multiple aliquots tomaintain a temperature greater than 55° C. and the completed carriersolution is heated to 65°-70° C. and mixed to homogeneity.

Subsequently, the solution is cooled to a temperature of between about45°-50° C. and a corticosteroid is then added to the solution and mixedto uniformity while maintaining a temperature of between about 45°-50°C. Total evaporative losses are kept below 1.0% w/w, and more preferablybelow 0.25% w/w, during compounding through the use of a suitablemanufacturing vessel with a pressure and/or vacuum rated lid that sealsonto the vessel.

Throughout the admixing process, the bulk solution may be analyzed toensure proper mixing and temperature of the solution. Once thecorticosteroid is added, the solution is mixed to uniformity. Thesolution is then filled into aerosol canisters while the solution ismaintained at a temperature of between about 42°-48° C. Preferably, thesolution is mixed for at least 30 minutes or more before being filledinto the dispensing canisters. The filled canisters are then chargedwith a propellant thereby forming a single-phase foamable composition.

According to one embodiment of the present invention the canisters aremade of metal having an internal resistance burst pressure of at least270 PSIG, more preferably tin or aluminum, and are lined to preventdegradation and corrosion. Another feature of the present invention isan aerosol valve, more preferably an inverted-dispensing valve. Yetanother feature of the present invention is an actuator and valvecombination capable of dispensing foam at a controlled rate withpreferred cosmetic characteristics.

Compositions

The present invention provides a greater than 36-month storage stable,foamable composition produced by the method described herein fortreating a corticosteroid-responsive condition, including skin diseasesand disorders, such as corticosteroid-responsive dermatoses. Thecomposition includes: a) a corticosteroid, or its pharmaceuticallyacceptable salts, esters, and solvates; b) an aliphatic alcohol; c) oneor more foam structuring agents (including one or more fatty alcohols,one or more non-ionic surfactants, or combinations thereof); d) apolyol; e) water; f) a can corrosion inhibitor; and g) a propellant. Thecomposition is preferably void of a buffer. It should be understood thatthe stable, therapeutic composition can consist essentially of, orconsist of, the above components.

The composition of the present invention is applied to the treatmentsite (after foaming) or a secondary site, such as a hand (afterfoaming), for application to the treatment site as a foam. Uponapplication, the composition is initially in the form of a mousse-likefoam which is engineered to break down at skin temperature under lowapplication shear allowing the halobetasol or other corticosteroid tosaturate the treatment site. The presently described system providesenhanced penetration of the halobetasol or other corticosteroid throughthe epidermis. The composition exhibits ideal characteristics betweentraditional rigid (mousse-like) and thermolabile (quick-break) foamsthat is achieved without buffering. It has been found that improvedstabilization of corticosteroid is achieved through addition of a smallamount of the can corrosion inhibitor benzoic acid. It should beunderstood that reference to the “can” herein refers to the canisterfrom which the composition is delivered.

The aliphatic alcohol may preferably be chosen from methyl, ethyl,isopropyl and butyl alcohols, and mixtures of two or more thereof. Inone embodiment, the aliphatic alcohol is ethyl alcohol. In embodiments,the aliphatic alcohol, such as ethyl alcohol, is included in thecomposition at between about 40-70%, 45-65%, 50-60%, or 55-60% w/w; orin an amount of about 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%,55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64% or 65% w/w.

The present composition further includes one or more foam structuringagents, such as one or more fatty alcohols. The one or more fattyalcohols included in the composition of the present invention have alinear or branched carbon backbone that has 6-22 carbon atoms. Inembodiments of the invention, the one or more fatty alcohols have alinear or branched carbon backbone that has 10-18 carbon atoms. Invarious embodiments the fatty alcohol is selected from the groupconsisting of lauryl alcohol, myristyl alcohol, cetyl alcohol, laurylalcohol, stearyl alcohol, octyldodecanol, and combinations thereof. Yetother fatty alcohols will be apparent to those of skill in the art. Inan embodiment, mixtures of cetyl alcohol and a stearyl alcohol arepreferred, for example cetostearyl alcohol.

In embodiments, the fatty alcohol, such as cetostearyl alcohol, isincluded in the composition at between about 0.05-1.0%, 0.06-0.95%,0.07-0.9%, 0.08-0.75%, 0.09-0.7%, 0.1-0.65%, 0.15-0.6%, 0.2-0.5%,0.2-0.4% or 0.2-0.3% w/w; or in an amount of about 0.15%, 0.16%, 0.17%,0.18%, 0.19%, 0.2%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%,0.28%, 0.29%, 0.3%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35% or 0.36% w/w.

The present composition further includes one or more foam structuringagents, such as one or more non-ionic surfactants. Non-ionic surfactantsthat may be used in the composition of the present invention generallyinclude ethoxylated alcohols. Non-ionic surfactants that may be used inthe composition of the present invention include glyceryl stearate, PEG100-stearate, polyoxyl-20-cetostearyl ether, glyceryl monooleate,glyceryl palmitostearate, polyoxyl-20-stearate, polyoxyl-40-stearate,polyoxyl-60-stearate, polyoxyl-80-stearate, polyoxyl-20-oleate,polyoxyl-40-oleate, polyoxyl-60-oleate, polyoxyl-80-oleate,polyoxyl-20-palmitate, polyoxyl-40-palmitate, polyoxyl-60-palmitate,polyoxyl-80-palmitate, polyoxyethylene (20) sorbitan monolaurate,polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20)sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate,laureth-2, laureth-4, laureth-6, and laureth-8. Yet other non-ionicsurfactants will be apparent to those of skill in the art. In apreferred embodiment, the non-ionic surfactant ispolyoxyl-20-cetostearyl ether. In embodiments, the non-ionic surfactant,such as polyoxyl-20-cetostearyl ether, is included in the composition atbetween about 0.05-1.0%, 0.06-0.95%, 0.07-0.9%, 0.08-0.75%, 0.09-0.7%,0.1-0.65%, 0.15-0.6%, 0.2-0.5%, 0.2-0.4% or 0.2-0.3% w/w; or in anamount of about 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.2%, 0.21%, 0.22%,0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.3%, 0.31%, 0.32%,0.33%, 0.34%, 0.35% or 0.36% w/w.

The present composition further includes one or more foam structuringagents including combinations of one or more fatty alcohols and one ormore non-ionic surfactants. The fatty alcohol component is selected fromthe group consisting of lauryl alcohol, myristyl alcohol, cetyl alcohol,lauryl alcohol, stearyl alcohol, octyldodecanol, and combinationsthereof. The non-ionic component is selected from the group consistingof glyceryl stearate, PEG 100-stearate, polyoxyl-20-cetostearyl ether,glyceryl monooleate, glyceryl palmitostearate, polyoxyl-20-stearate,polyoxyl-40-stearate, polyoxyl-60-stearate, polyoxyl-80-stearate,polyoxyl-20-oleate, polyoxyl-40-oleate, polyoxyl-60-oleate,polyoxyl-80-oleate, polyoxyl-20-palmitate, polyoxyl-40-palmitate,polyoxyl-60-palmitate, polyoxyl-80-palmitate, polyoxyethylene (20)sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate,polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20)sorbitan monooleate, laureth-2, laureth-4, laureth-6, and laureth-8. Yetother fatty alcohols and other non-ionic surfactants will be apparent tothose skilled in the art. In a preferred embodiment, the fatty alcoholand non-ionic surfactant combination includes cetyl alcohol, stearylalcohol, and one or more of polyoxyethylene (20) sorbitan monolaurate,polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20)sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate, forexample, Emulsifying Wax, NF.

In embodiments, the foam structuring agent(s) is included in thecomposition at between about 0.1-4.0%, 0.1-3.5%, 0.1-3.0%, 0.1-2.5%,0.1-2.0%, 0.5-2.0%, 1.0-2.0%, 1.5-2.0% or 1.6-1.9% w/w; or in an amountof about 1.05%, 1.1%, 1.15%, 1.2%, 1.25%, 1.3%, 1.35%, 1.4%, 1.45%,1.5%, 1.55%, 1.6%, 1.65%, 1.7%, 1.75%, 1.8%, 1.85%, 1.9%, 1.95% or 2.0%w/w.

In embodiments, Emulsifying Wax, NF, is included in the composition atbetween about 0.1-4.0%, 0.1-3.5%, 0.1-3.0%, 0.1-2.5%, 0.1-2.0%,0.5-2.0%, 1.0-2.0%, 1.0-1.5% or 1.0-1.1% w/w; or in an amount of about0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.05%, 1.1%, 1.15%, 1.2%, 1.25%,1.3%, 1.35%, 1.4%, 1.45%, 1.5%, 1.55%, 1.6%, 1.65% or 1.70%, 1.75%,1.8%, 1.85%, 1.9%, 1.95% or 2.0% w/w.

The polyol component of the composition may function as a solubilityenhancer for the corticosteroid and may have traditional humectantproperties. Such polyols may include materials such as glycerin,propylene glycol, butylene glycol, dipropylene glycol, pentylene glycol,hexylene glycol, polyethylene glycol, and the like; and these polyolmaterials maybe used either singly or in combination in the preparationsof the present invention. In a preferred embodiment, the polyol ispropylene glycol. In embodiments, the polyol solubility enhancer isincluded in the composition at between about 1-10%, 2-8%, 3-7%, or 4-6%w/w; or in an amount of about 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%,4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5% or10.0% w/w; or in an amount of about 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%,4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.25%, 5.3%, 5.4%, 5.5%, 5.6%,5.7%, 5.9%, 6.0%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6%, 6.7%, 6.8%, 6.9%or 7.0% w/w.

The composition of the present invention maybe contained in anddispensed from a container capable of withstanding the pressure of thepropellant gas and having an appropriate valve and actuator fordispensing the composition as a foam under pressure. If the container ismade of a material such as aluminum or tin that is likely to suffercorrosion under the action of the composition, in the event the internallining suffers a breach, the composition may include a single corrosioninhibitor as an additive. Suitable corrosion inhibitors include organicacids, such as but not limited to sorbic acid, benzoic acid, formicacid, acetic acid, propionic acid, butyric acid, valeric acid, caproicacid, oxalic acid, lactic acid, malic acid, citric acid and carbonicacid. In embodiments, the can corrosion inhibitor is included in thecomposition at less than about 0.0015%, 0.001%, 0.0009%, 0.0008%,0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001%, w/w.

The propellant used may be chosen from conventional aerosol propellants.Thus, one may select the propellant from propane, n-butane, isobutane,n-pentane, isopentane, dichloro difluoro methane, dichloro tetrafluoroethane, octafluoro cyclobutane, 1,1,1,2-tetrafluoroethane,1,1-difluoroethane, 1,1,1,2,3,3,3-heptafluoropropane and mixtures of twoor more thereof. The propellant level should be adjusted to optimize thequality of the foam and to produce traditional rigid (mousse-like) andthermolabile (quick-break) characteristics. In embodiments, thepropellant is included in the composition at between about 2.75-6.25%,3-6%, or 3.25-5.75% w/w; or in an amount of about 2.75%, 3%, 3.25%,3.5%, 3.75%, 4%, 4.25%, 4.5%, 4.75%, 5%, 5.25%, 5.5%, 5.75%, 6%, or6.25% w/w.

The present composition further includes an aqueous component, such aswater. In embodiments, water is included in the composition at betweenabout 25-45%, 30-40% or 35-40% w/w; or in an amount of about 25%, 26%,27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%,41%, 42%, 43%, 44% or 45% w/w.

In specific embodiments of the present invention, the foregoingingredients are present in particular ratios. A number of formulationsmay be prepared in accord with the present invention shown in TablesI-VI below, which list compositional ranges for such formulations.

TABLE I Formulation Component Ranges Component % w/w Aliphatic alcohol40-60 Foam structuring agents (fatty alcohols, non- 0.1-4.0 ionicsurfactants, and combinations thereof) Polyol solubility enhancer  1-10Water 30-40 Corrosion inhibitor less than 0.001

TABLE II Formulation Component Ranges Component % w/w Aliphatic alcohol50-60 Fatty alcohol and/or non-ionic surfactant 0.1-1.0 Emulsifying Wax,NF 0.5-2.0 Polyol solubility enhancer 2-8 Water 35-40 Corrosioninhibitor less than 0.001

TABLE III Formulation Component Ranges Component % w/w Aliphatic alcohol50-60 Emulsifying Wax, NF 0.5-2.0 Fatty alcohol 0.1-0.4 Non-ionicsurfactant 0.1-0.4 Polyol solubility enhancer 2-8 Water 35-40 Corrosioninhibitor less than 0.001

TABLE IV Formulation Component Ranges Component % w/w Aliphatic alcohol50-60 Emulsifying Wax, NF 1.0-1.1 Fatty alcohol 0.2-0.3 Non-ionicsurfactant 0.2-0.3 Polyol solubility enhancer 2-8 Water 35-40 Corrosioninhibitor less than 0.001

TABLE V Formulation Component Ranges Component % w/w Ethyl alcohol 40-60Emulsifying Wax, NF 0.1-5.0 Cetostearyl alcohol 0.05-1.0  Polyoxyl 20cetostearyl ether 0.05-1.0  Propylene glycol  1-10 Water 30-40 Benzoicacid less than 0.001

TABLE VI Corticosteroid Formulations Component % w/w Corticosteroid 0.05Ethyl alcohol 50-60 Emulsifying Wax, NF 1.0-1.1 Cetostearyl alcohol0.2-0.3 Polyoxyl 20 cetostearyl ether 0.2-0.3 Propylene glycol 2-8 Water35-40 Benzoic acid less than 0.001

Preparations based upon the ratios set forth in Tables I-VI, include, orwill further include the corticosteroid material and a propellant, andmay also include ancillary ingredients such as preservatives,fragrances, coloring agents, viscosity control agents and the like. Thecorticosteroid is preferably present in an amount of about 0.01-1.0% w/wmore preferably about 0.05-0.2% w/w. In embodiments, corticosteroids foruse in the present invention include, by way of illustration and in noway limiting, the following: methylprednisolone, hydrocortisone,prednisolone, clobetasone, hydrocortisone butyrate, flumetasone,fluocortin, fluperolone, fluorometholone, fluprednidene, desonide,triamcinolone, alclometasone, hydrocortisone buteprate, dexamethasone,clocortolone, betamethasone, fluclorolone, desoximetasone, fluocinoloneacetonide, fluocortolone, diflucortolone, fludroxycortide, fluocinonide,budesonide, diflorasone, amcinonide, halometasone, mometasone furoate,methylprednisolone aceponate, beclometasone, hydrocortisone aceponate,fluticasone, prednicarbate, difluprednate, halobetasol, resocortolbutyrate, clobetasol and halcinonide. In a preferred embodiment, thecorticosteroid is halobetasol, such as halobetasol propionate.

Unlike typical foam formulations, the composition of the presentinvention does not include a buffer system. As such, the composition isvoid of a traditional buffer. During preparation the minute amount ofthe can corrosion inhibitor added serves to maintain the product at a pHin the general range of about 4.0-6.3 and preferably about 5.0-5.5 atthe time of manufacture. In embodiments, the preferred can corrosioninhibitor is benzoic acid at less than about 0.0015%, 0.001% or 0.0005%w/w.

Upon dispensing from the can the composition of the present invention isfound to produce a rigid, mousse-like foam that remains thermally stableon the surface of the skin until applied with light shear to theapplication site. The thermal stability of the foam at about 32-37° C.has been demonstrated for up to at least 600 seconds. The thermalstability of the foam at about 20-25° C. has been demonstrated for up toat least 1200 seconds. Unexpectedly, it remains rigid and mousse-like atskin temperature but the foam behaves like a traditional thermolabile(quick-break) foam during application of shear forces, allowing for easeof use and application at the treatment site.

The composition of the present invention is found to exhibit very goodstability under storage conditions. As is known in the art,corticosteroids may degrade under storage conditions. For example,halobetasol propionate can degrade under storage conditions with some ofthe degradation products or impurities produced including: halobetasolA₁₆ analog; and halobetasol spiro analog.

The amount of degradation products of halobetasol material, such asdegradation products of halobetasol propionate, is directly related tothe amount of degradation of the halobetasol material.

Compositions of the present invention are storage stable such that theamount of degradation products of a halobetasol material therein afterstorage for six months at 40° C. is less than 5% and at storage for 24months at 25° C. is less than 2% of the total amount of the halobetasolmaterial contained therein at the time of manufacture.

The storage stability of compositions of the present invention can bedemonstrated by the pH stability of the formulation, assay of the amountof halobetasol material, such as halobetasol propionate, and/or by assayof the amount of one or more degradation products of the halobetasolmaterial.

In one embodiment, the composition of the present invention exhibits anacceptable shelf-life of greater than about 36, 39, 42, 45, 48 or moremonths. For example, in embodiments, the shelf-life of the presentinvention can be projected at greater than 36 months using standardanalysis techniques, such as those described in the InternationalConference on Harmonisation of Technical Requirements for Registrationof Pharmaceuticals for Human Use (ICH) Q1A (R2) guidance for industry,Stability Testing of New Drug Substances and Products (available on theWorld Wide Web atfda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073369.pdf; and incorporated by reference herein in its entirety in particularfor its teaching of analysis techniques that should be used). Accordingto the guidance it is normally unnecessary to perform a formalstatistical analysis on data that show little degradation and littlevariability. The recommended approach for analyzing data expected tochange with time is to apply the 95 percent, one-sided confidence limitto the mean and to determine the time at which the confidence intervalintersects the acceptance criterion.

In various embodiments, the composition of the present invention isstable, having an acceptable shelf-life of at least six months. In someembodiments the composition has an acceptable shelf-life of at least oneyear. In some embodiments the composition has an acceptable shelf-lifeof at least 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48 or moremonths at ambient temperature as determined by the analysis methoddescribed above (and used in Example 4 herein) in the InternationalConference on Harmonisation of Technical Requirements for Registrationof Pharmaceuticals for Human Use (ICH) Q1A (R2) guidance for industry,Stability Testing of New Drug Substances and Products.

In some embodiments, compositions of the present invention are storagestable such that the amount of degradation products of a halobetasolmaterial therein after storage for at least 15, 18, 21, 24, 27, 30, 33,36, 39, 42, 45 or 48 months at 40° C. is less than about 10%, 9%, 8%,7%, 6%, 5%, 4%, 3%, 2% or 1% of the total amount of the halobetasolmaterial contained therein at the time of manufacture.

Methods of Treatment

In another aspect, the present invention provides a method for treatinga subject having, or at risk of having, a corticosteroid-responsivecondition, such as a skin disease or disorder. The method includestopically administering to the subject in need thereof a foamablecomposition manufactured as described herein, thereby treating the skindisorder or disease.

Particular corticosteroid-responsive conditions, such ascorticosteroid-responsive dermatoses, that are treated using methods andtopical foamable compositions of the present invention include but arenot limited to inflammatory diseases such as allergic contactdermatitis, eczema, asteatotic eczema, discoid eczema, infantile eczemaand diaper dermatitis, psoriasis; including plaque psoriasis,palmoplantar psoriasis, etc., seborrheic dermatitis, atopic dermatitis,dermatitis herpetiformis, neurodermatitis, lichen simplex chronicus,lichen planus, subacute cutaneous lupus erythematosus, urticaria,discoid lupus erythematosus, chronic hypertrophic lichen planus,granuloma annulare, keloid scars, reactions to insect and spider bites,pityriasis rosea, erythema, and pruritus.

Methods and compositions of the present invention can be used forprophylaxis as well as amelioration of signs and/or symptoms ofcorticosteroid-responsive dermatoses. The terms “treating” and“treatment” used to refer to treatment of a corticosteroid-responsivedermatosis in a patient include preventing, inhibiting or amelioratingthe corticosteroid-responsive dermatosis in the patient, such as slowingprogression of the corticosteroid-responsive dermatosis and/or reducingor ameliorating a sign or symptom of the corticosteroid-responsivedermatosis.

A therapeutically effective amount of a topical foam composition of thepresent invention is an amount which has a beneficial effect on acorticosteroid-responsive dermatosis in a patient being treated. Forexample, a therapeutically effective amount of a composition of thepresent invention is effective to detectably decrease inflammation,crusting, scaling, erythema, induration, skin thickening and/or itchingin a patient being treated for corticosteroid-responsive dermatosis.

Patients are identified as having, or at risk of having, acorticosteroid-responsive dermatosis using well-known medical diagnostictechniques.

The term “patient” or “subject” refers to an individual in need oftreatment for a corticosteroid-responsive dermatosis. Human patients areparticularly referred to herein although the terms are not limited tohumans and encompass mammals as well as other animals, such as, but notlimited to, non-human primates, cats, dogs, cows, horses, rodents, pigs,sheep, goats and poultry, and other animals in need of treatment for acorticosteroid-responsive dermatosis seen in veterinary practice.

The composition of the present invention may be administered acutely orover a period of weeks. For example, a composition as described hereinmay be topically administered at least once or twice, a day.Administration may include multiple doses administered topically over aperiod of days or weeks, such as for treatment ofcorticosteroid-responsive dermatosis or as multiple short courses oftherapy over a period of months or years to prevent recurrence or flaresof the inflammatory disease.

A therapeutically effective amount of a composition according to thepresent invention will vary depending on the particular formulationused, the severity of the corticosteroid-responsive dermatosis to betreated, the species of the patient, the age and sex of the subject andthe general physical characteristics of the patient to be treated. Oneof skill in the art could determine a therapeutically effective amountin view of these and other considerations typical in medical practice.In general it is contemplated that a therapeutically effective amount,applied topically, would be determined by the area of body surfaceinvolved in the disease or condition and would likely be in the range of0.5 gm-3.5 gm per application if administered twice a day. Further,dosage may be adjusted depending on whether treatment is to be acute orcontinuing.

Methods of treatment according to the present invention optionallyinclude preparation of the area to be treated by cleansing with asuitable surfactant containing composition. The product can also be usedin conjunction with a skin moisturizer.

The following examples are provided to further illustrate theembodiments of the present invention, but are not intended to limit thescope of the invention. While they are typical of those that might beused, other procedures, methodologies, or techniques known to thoseskilled in the art may alternatively be used.

EXAMPLE 1 Foamable Halobetasol Propionate Composition

A composition was prepared in accord with the present inventionutilizing the formulation of Table VI above. Listed in Table VI is aspecific composition based upon the ranges set forth hereinabove inTable I.

In this procedure as described in detail herein, a carrier solution isprepared by mixing and heating ethyl alcohol to between about 65°-70°C., adding benzoic acid, propylene glycol, Polyoxyl 20 cetostearylether, cetostearyl alcohol, and emulsifying wax and mixing to uniformitywhile maintaining a temperature of between about 65°-70° C. Water isadded in multiple aliquots to maintain a temperature greater than 55° C.and the completed carrier solution is heated to 65°-70° C. The carriersolution is prepared in a vessel with a pressure and/or vacuum rated lidthat seals onto the vessel in order to minimize evaporative lossesduring compounding. Then the carrier is cooled to about 45°-50° C. andthe halobetasol propionate is added and mixed to uniformity. Thesolution is then filled into canisters while maintaining a temperatureof between about 42°-48° C. and subsequently charged with propellant.

EXAMPLE 2 Skin Hydration and Transepidermal Water Loss (TEWL)

A series of studies was carried out to evaluate the properties andadvantages of the composition of the present invention. These studieswere carried out utilizing a preparation having a formulation in accordwith Table VI as prepared by the procedure set forth above. In a firststudy, skin hydration was determined by use of an IBS Skicon-200Conductance Meter equipped with a Measurement Technologies probe [unit2283, probe A] to further enhance its ability to measure changes in skinsurface hydration.

The data confirm that the composition of the present invention did notincrease skin hydration when applied to shaved skin and was notconsidered to be occlusive. In fact, the composition decreased skinhydration (i.e., dehydrated) when applied to shaved skin.

A further study was carried out measuring transepidermal water loss(TEWL) of skin treated with the composition of the present invention.Computerized evaporimetry was measured with a recently calibratedcyberDERM RG1 Evaporimeter System (Broomall, Pa.) with TEWL Probes [unitRG1-09-048, probes 715 & 716] that were manufactured by CortexTechnology (Hadsund, Denmark).

The data confirm that the composition of the present invention whenapplied to shaved skin did not decrease TEWL.

Increased hydration of the skin is typically associated with anincreased penetration of the active pharmaceutical ingredient (i.e.,halobetasol) and consequently and increased efficacy. Similarly, adecrease in TEWL is associated with increased hydration, an increasedpenetration of the active pharmaceutical ingredient (i.e., halobetasol)and consequently an increased efficacy.

Unexpectedly, the composition tested does not appear to be acting as anocclusive since TEWL was not decreased and there was no increase in skinhydration.

EXAMPLE 3 Clinical Efficacy

A further experimental study evaluated the clinical efficacy of thecomposition of the present invention having the formulation of Table VI,described above, in the treatment of subjects with plaque psoriasis.

Results

52% of psoriasis subjects treated with the composition of the presentinvention having the formulation described above, and 0.0% of subjectstreated with an identical composition void of halobetasol (ControlVehicle), achieved “treatment success”.

Definitions:

Overall Disease Severity (ODS): At every visit, the overall severity ofa subject's psoriasis in the Treatment Area, taking into considerationthe three individual clinical signs of psoriasis (scaling, erythema, andplaque elevation) was assessed using a five-point scale ranging from0=clear to 4=severe/very severe. To be enrolled in the study thesubjects had to have at least a moderate ODS score (≥3).

Clear (0) Scaling No evidence of scaling. Erythema No erythema(hyperpigmentation may be present). Plaque No evidence of plaqueelevation above normal skin level. elevation

Almost Clear (1) Scaling Limited amount of very fine scales partiallycovers some of the plaques. Erythema Faint red coloration. Plaque Veryslight elevation above normal skin level, easier felt elevation thanseen.

Mild (2) Scaling Mainly fine scales; some plaques are partially covered.Erythema Light red coloration. Plaque Slight but definite elevationabove normal skin level, elevation typically with edges that areindistinct or sloped, on some of the plaques.

Moderate (3) Scaling Somewhat coarser scales predominate; most plaquesare partially covered. Erythema Moderate red coloration. Plaque Moderateelevation with rounded or sloped edges on most elevation of the plaques.

Severe/Very Severe (4) Scaling Coarse, thick tenacious scalespredominate; virtually all or all plaques are covered; rough surface.Erythema Dusky to deep red coloration. Plaque Marked to very markedelevation, with hard to very hard elevation sharp edges on virtually allor all of the plaques.

Clinical Signs of Plaque Psoriasis: At every visit, the average severityof each of the three key characteristics of plaque psoriasis (scaling,erythema and plaque elevation) in the Treatment Area was assessed usinga five-point scale ranging from 0=clear to 4=severe/very severe.

Scaling: 0 Clear No evidence of scaling. 1 Almost Limited amount of veryfine scales partially covers clear some of the plaques. 2 Mild Mainlyfine scales predominate; some plaques are partially covered. 3 ModerateSomewhat coarser scales predominate; most plaques are partially covered.4 Severe/ Coarse, thick tenacious scales predominate; virtually Verysevere all or all plaques are covered; rough surface.

Erythema: 0 Clear No erythema (hyperpigmentation may be present). 1Almost Faint red coloration. clear 2 Mild Light red coloration. 3Moderate Moderate red coloration. 4 Severe/ Dusky to deep redcoloration. Very severe

Plaque Elevation: 0 Clear No evidence of plaque elevation above normalskin level. 1 Almost Very slight elevation above normal skin level,easier clear felt than seen. 2 Mild Slight but definite elevation abovenormal skin level, typically with edges that are indistinct or sloped,on some of the plaques. 3 Moderate Moderate elevation with rounded orsloped edges on most of the plaques. 4 Severe/ Marked to very markedelevation, with hard to very Very severe hard sharp edges on virtuallyall or all of the plaques.

Pruritus: At every visit, the severity of pruritus was scored on asix-point scale from 0=none to 5=severe according to the followingscale.

Pruritus 0 None No evidence of itching. 1 Mild Only aware of itching attimes, only present when relaxing, not present when focused on otheractivities. 2 Mild to Intermediate between 1 and 3. Moderate 3 ModerateOften aware of itching, annoying, sometimes disturbs sleep and daytimeactivities. 4 Moderate Intermediate between 3 and 5. to Severe 5 SevereConstant itching, distressing; frequent sleep disturbance, interfereswith activities.

To be enrolled into the study, subjects had to have at least moderateODS score (at least 3). All ITT subjects satisfied that requirement withat least 85% of each treatment group (HBP: 87% or 20/23; VEH: 85% or17/20) having moderate ODS, with the remainder of subjects havingsevere/very severe ODS

In this study “treatment success” is indicated by a score of 0 or 1 foroverall disease severity (ODS) and the clinical signs and symptoms ofpsoriasis. Further, the term “improved” refers to at least a two (2)grade decrease in severity score relative to Baseline for overalldisease severity (ODS) and the clinical signs and symptoms of psoriasis.Note: Dichotomization of scores for clinical signs and symptoms ofpsoriasis will exclude subjects with Baseline scores of 0 or 1 unlessthe corresponding sign score at Day 8 or Day 15 is >1.

As illustrated in FIG. 1, the ODS score remained unchanged (change=0) atDay 15 for the majority of vehicle group subjects (18/20; 90%) with theremaining subjects experiencing, at most, a one grade improvement. Only21.7% (5/23) of the HBP subjects had no change in ODS score at Day 15with the remaining subjects having a one to three grade decrease inscore.

It was anticipated that a halobetasol cream would be more efficaciousthan halobetasol foam because creams are determined to be moreocclusive. However, efficacy results for the composition set forth inTable VI were materially better than those obtained in the studies thatsupported Ultravate® Cream (halobetasol propionate) approval by the FDA.

In fact, “treatment success” results for the composition set forth inTable VI, were determined to be equal to or better than those publishedfor all other forms of Class 1 topical steroid products containinghalobetasol, fluocinonide and even what is believed to be the mostpotent steroid: clobetasol propionate. (See Table VII).

TABLE VII Treatment Success FDA Approved Class 1 Topical CorticosteroidProducts (Study Drugs1-9) and the Composition set forth in Table IIherein (Study Drugs 10 and 11) Treatment Success (or Improved) at 2Weeks** Year Study Drug Results Control Drug Results Approved 1Ultravate ® Cream 3/38 (7.9%) Vehicle 0/39 (0.0%) 1991 (halobetasolpropionate) (Study 1) 2 Ultravate ® Cream 7/40 (17.5%) Vehicle 0/40(0.0%) 1991 (halobetasol propionate) (Study 2) 3 Temovate ® E 12/51(22%) Vehicle 1/46 (2%) 1994 (clobetasol propionate) (Includes ITTCleared and Excellent) 4 Clobetasol propionate 30/82 (36.6%) Temovate E33/81 (40.7%) 2003 Lotion ITT (clobetasol propionate) 4 week. study 5Clobetasol propionate 27/76 (35.5%) Temovate E 32/75 (42.7%) 2003 LotionPP (clobetasol propionate) 4 week study 6 Vanos ® (fluocinonide) 19/107(18%) Vanos (fluocinonide) 33/107 (31%) 2005 QD ITT BID 7 Vanos ®(fluocinonide) 18/90 (20%) Vanos (fluocinonide) 31/97 (32%) 2005 QD PPBID 8 Olux ® E Foam 41/253 (16%) Temovate Ointment 38/121 (31%) 2007(clobetasol propionate) (clobetasol propionate) ITT 9 Olux ® E(clobetasol 39/234 (17%) Temovate Ointment 34/111 (31%) 2007 propionate)PP (clobetasol propionate) 10 Present Invention 12/23 (52.2%) Vehicle0/20 (0.0%) Currently In (halobetasol propionate) Development ITT 11Present Invention 12/22 (54.5%) Vehicle 0/20 (0.0%) Currently In(halobetasol propionate) Development PP **Note: Studies 4 and 5 showresults collected after 4 weeks of treatment. All the rest show resultsafter only 2 weeks of treatment. BID = Twice per day; ITT = Intent toTreat Population; PP = Per Protocol Population; QD = Once per day

It should be noted that over the years the FDA has changed theparameters defining clinical “success” and has progressively elevatedthe efficacy standard for “treatment success”. The results obtained withthe present halobetasol propionate foam composition were unexpectedlystrong. The Ultravate® Cream results as shown in the first two rows ofthe Treatment Success Table VII were filed with the FDA as a basis ofthe NDA approval. It should also be noted that the results achieved withthe halobetasol propionate foam composition of the present invention aresuperior to those achieved through the use of the Ultravate® Cream andare as good as or better than any of the other Class 1 topicalcorticosteroids.

Clobetasol propionate is generally believed to be a more potent steroidmolecule than halobetasol propionate. As shown in Table VII, the resultsof a clinical trial that served as the basis of the FDA approval ofOlux® E Foam reported 16% of the Olux® E Foam treated subjects and 31%of the Control subjects receiving Temovate® Ointment (0.05% clobetasolpropionate) achieved “treatment success”. Unexpectedly, inclusion ofhalobetasol propionate (as opposed to clobetasol propionate) in a foamformulation comparable to Olux® E Foam (which is not produced asdescribed herein) produced a “treatment success” in 52.2% of thosepatients treated as compared to 16% of those who had been treated withOlux® E Foam.

The “treatment success” rate of 52% for the composition set forth inTable VI is unexpected because the similar Olux® E Foam formulationcontaining the more potent molecule (i.e., clobetasol propionate) onlyachieved a 16% rate. These results are indeed unexpected given therelative potencies of halobetasol propionate and clobetasol propionate.One would expect a comparable composition including halobetasol (i.e.,the formulation of Table VI), which is considered less potent thanclobetasol, to be less efficacious than Olux® E Foam. These results showunexpected beneficial therapeutic effects were achieved through use ofthe composition of the present invention.

EXAMPLE 4 Formulation Stability

A composition was prepared in accord with the present inventionutilizing the formulation of Table VI above. The composition was filledinto canisters that were charged with propellant. The contents of thecanister were analyzed by high-performance liquid chromatography (HPLC)for halobetasol propionate content and associated degradation products.The pH of the canister contents was also measured. Additional canisterswere placed on stability at 25°±2° C. and 60%±5% relative humidity, theICH long-term storage condition. Fresh samples were analyzed after 1-,3-, 6-, 9-, 12-, and 18-months of storage.

The assay results were plotted against the storage duration in months.The linear regression was determined for the assay data. The 95%one-side lower confidence interval was determined for the linearregression. The resulting predicted shelf-life was unexpectedly greaterthan 36 months as shown in FIG. 3.

The degradant results were plotted against the storage duration inmonths. The linear regression was determined for the degradant data. The95% one-side upper confidence interval was determined for the linearregression. The resulting predicted shelf-life was unexpectedly greaterthan 36 months as shown in FIG. 4.

Unexpectedly, no significant change and no trending were observed withthe pH data for the unbuffered formulation. Therefore, no formalstatistical analysis was performed on the pH data in order to projectthe shelf-life. The pH data are shown in FIG. 5.

Although the invention has been described with reference to the aboveexample, it will be understood that modifications and variations areencompassed within the spirit and scope of the invention. Accordingly,the invention is limited only by the following claims.

What is claimed is:
 1. A storage stable, foamable composition comprisingon a weight basis: a) 0.02 to 0.10% halobetasol or its pharmaceuticallyacceptable salts, esters, and solvates; b) 40 to 60% ethyl alcohol; c)0.1 to 5.0% Emulsifying Wax, NF; d) 0.05 to 1.0% cetostearyl alcohol; e)0.05 to 1.0% polyoxyl 20 cetostearyl ether; f) 1 to 10% propyleneglycol; g) 30 to 40% water; and h) greater than 0.0% and less than0.0005% benzoic acid, wherein the composition has a pH of between about4.0 to 6.3, and wherein the composition is produced by: forming ahomogenous solution including (b)-(h), wherein the solution is formed ina single batch vessel at a temperature of between about 55° to 75° C.while minimizing the evaporative losses; cooling the homogenous solutionto a temperature of between about 40° to 55° C.; adding halobetasol, ora pharmaceutically acceptable salt, ester, or solvate thereof, to thecooled solution and forming a homogenous solution while maintaining atemperature of between about 40° to 55° C.; filling an aerosol canisterwith the homogenous solution while the solution is maintained at atemperature of between about 40° to 50° C.; and charging the canisterwith the propellant thereby forming the foamable composition.
 2. Thecomposition of claim 1, wherein the ethyl alcohol and benzoic acid arecombined before adding the propylene glycol, polyoxyl 20 cetostearylether, cetostearyl alcohol and water.
 3. The composition of claim 2,wherein the benzoic acid is added to the ethyl alcohol which is heatedto at least about 55° C. before addition of the benzoic acid.
 4. Thecomposition of claim 1, wherein the homogenous solution including(b)-(h) is maintained at a temperature of between about 65° to 70° C. 5.The composition of claim 1, wherein the homogenous solution including(b)-(h) is cooled to a temperature of between about 45° to 50° C.
 6. Thecomposition of claim 1, wherein filling is performed while maintainingthe solution at a temperature of between about 42° to 48° C.
 7. Thecomposition of claim 1, wherein the homogenous solution including(b)-(h) is prepared in a suitable vessel to keep evaporative lossesbelow 0.25% w/w during compounding.
 8. The composition of claim 1,wherein the halobetasol remains stable for at least three months at 40°C.
 9. The composition of claim 1, wherein the propellant is propane,n-butane, isobutane, or combinations thereof, at 3.25 to 5.75% w/w.